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Why Do Some Teens Become Binge Drinkers? Algorithms Answer.

The first time I got drunk I was 15. It was in a hotel room in Paris, on a trip with my high school French Club, drinking vodka and Orangina from a plastic bottle. I remember looking at my blurry reflection in the bathroom mirror and thinking, So this is what being drunk is. I didn’t hate it. I drank a few more times that year, and then pretty steadily for the next two. I had one blackout night in a friend’s basement. Then came college, where everything escalated. It honestly makes me queasy right now to think about what I put my body through.

But it was fun. And it didn’t lead to anything horrible. I did well academically, went to grad school, found (mostly) gainful employment. I’m 30 now and, knock on wood, don’t have any health problems.

My story is typical. “We tend not to want to say this out loud to teenagers, but most people who tried drugs don’t get addicted,” says Hugh Garavan, a cognitive neuroscientist at the University of Vermont. “Most kids have tried alcohol by age 14, and most kids don’t develop a problem. Same with cigarettes and same with cocaine. But there’s a certain subset who do, and we don’t have a clue what it is about them.”

Scientists have pinpointed lots of factors that increase the risk of alcohol misuse — a bit. Adolescents who are anxious or impulsive, for example, tend to be at higher risk. Same for those who carry certain genetic variants (dubbed ‘SNPs’) in their genome, and for kids who are abused or neglected. But most studies haven’t looked at enough factors, or at enough kids, to make predictions with much oomph. “It’s hard to look at all of it, but we have this luxury,” Garavan says.

In today’s issue of Nature, Garavan and his colleagues present a new predictive model based on an enormous amount of data—brain scans, genetic screens, personality trait tests, and family and medical histories—from 2,400 teenagers in Europe. The model isn’t by any means a crystal ball, but it can guess which 14-year-olds will become binge drinkers by age 16 with odds far better than chance.

Garavan is one of the leaders of the IMAGEN Consortium, a €10 million-plus study following teenagers at eight different sites in Europe with the aim of pinpointing biological and environmental factors that influence adolescent mental health. The Consortium has published several dozen papers related to various relationships between brain activity, genetics, and behavior at age 14. This paper is the first to look at whether data collected from the volunteers at age 14 could predict their behaviors at age 16. Turns out, it can.

Part of the reason this study is powerful is because of its math. The researchers’ task was retrospective prediction: Knowing what happened to a kid at age 16 and looking back at a massive pool of data from age 14 to see what could have predicted it. In this case, though, the massive pool of data posed a problem. “With a gazillion variables that could potentially predict, there’s a real risk that you’ll find associations just by chance,” Garavan says.

To get around this, researchers used a machine-learning method that separated the data into many subgroups of participants. They’d develop a predictive model for one subgroup, then test it on another subgroup to see if the relationships held. And then they repeated the process on another group, and another and another. In the end, the best model relied on several dozen variables, as shown in this chart:

Whelan et al., Nature 2014
Whelan et al., Nature 2014 (Click to enlarge)

The variables listed on the left hand side refer to what participants scored at age 14. (For this analysis, the researchers only looked at 14-year-olds who were not drinkers, reporting two or fewer alcoholic drinks in their lifetime.) The factors with the most negative correlation coefficients (that is, the ones with lines furthest to the left) are those that, on their own, most strongly predict alcohol misuse at age 16. The variables with the most positive correlation coefficients (with lines furthest to the right) are most protective against alcohol misuse.

So, according to the model, if a 14-year-old non-drinker has an “extravagant” personality, which is characterized by grandiosity, exuberance and impulsivity, he or she will have a higher risk of becoming a binge drinker by age 16. (The researchers defined binge drinking as having at least three binge-drinking episodes leading to drunkenness.) In contrast, a 14-year-old non-drinker with “conscientious” personality scores will be at a lower risk of becoming a binger.

Under the “Brain” heading, you’ll see “Parenchymal volume,” which is the volume of the whole brain. In other words, kids who have larger brains at age 14 are at a higher risk of binging at age 16. This is intriguing, Garavan says, because the brain typically gets smaller in adolescence, when connections that aren’t used get pruned away. “So their brains seem to be less mature.”

By weighing these several dozen factors together, the mathematical model could correctly classify 66 percent of the binge drinkers and 73 percent of the non-binge drinkers, which is significantly better than chance. (About 45 percent of the 14-year-olds in this model went on to become binge drinkers at age 16.)

“It is a great example of how machine learning can provide novel insight in ways that have big potential for clinical impact,” says Dennis Wall of Stanford University, who was not involved in the study but is using similar techniques to diagnose autism. The new model’s predictive power is somewhat modest, Wall adds, “but even this could have meaningful impact.”

To me, what’s most interesting about the study is that the variables most difficult and expensive to obtain — the genetic markers and brain signatures — are far less important to the model’s predictive power than things like personal history and personality traits. Garavan says his team created a version of the model with only the history and personality measures, and “on their own they do a pretty good job.” That’s good news because it means that doctors, parents or educators might be able to spot high-risk teens without much more than a survey or two.

One big caveat with this particular study is that it stops at age 16. For most teens, drinking does not. So the IMAGEN team brought many of the same teens back into the lab at age 18 and is now working on comparisons of all of this data at age 14, 16, and 18. If the researchers get funding, they’ll look again at age 23.

As I do with most people I interview, I asked Garavan what message he would most like to get across to the general public about this study. He answered with what he doesn’t want to communicate.

“What I don’t want to get across is that we have figured out some secret formula: Give us your kids and we’ll tell you what to do,” he says. Teenage drinking “is not just evil kids choosing to do bad things. There are these preexisting risk factors of vulnerabilities, and we can measure them.”

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The genes that built a home

Shape of an oldfield mouse burrow. From Weber et al, Nature.

To catch oldfield mice, Hopi Hoekstra needed a long tube and quick reflexes. The mice dig burrows in sandy fields and beaches of the southern USA. They build a round nest chamber, an entrance tunnel that connects it to the outside world, and an escape tunnel that extends in the opposite direction and ends just below the surface. If Hoekstra put a tube down an entrance and blew through it, a mouse would erupt from of its escape hatch in a shower of sand.* And because the burrows are so standardized, it was easy to predict where the mouse will emerge.

Back in the lab, Hoekstra’s team, including Jesse Weber and Brant Peterson, made a surprising discovery. The shape of the burrows is controlled by a surprisingly small number of genes. Three small parts of the mouse’s genome control the size of its entrance tunnel, each one accounting for around 3 centimetres of length. And just one small region determines whether or not the mouse builds an escape tunnel.

We’re used to the fact that genes can shape bodies and behaviour, and that scientists can find these associations. But our bodies and behaviour reshape the world around us. Beavers, for example, build dams, which means that beaver genes can redirect the flow of entire rivers.

This is what Richard Dawkins called an “extended phenotype”. A creature’s phenotype is the collection of its traits, from its body shape to its behaviour. Its extended phenotype is the stamp it make upon its environment, such as beaver dams, bird nests, spider webs… and mouse burrows. None of these things have genes themselves, but genes clearly influence their construction. In 2004, Dawkins wrote, “Twenty-one years ago, I said that nobody had done a genetic study using animal artefacts as the phenotype. I think that is still true.”

It’s not true anymore: Hoekstra’s team have done exactly what Dawkins asked for. They’ve explored the genetics of an inanimate object.

The project is close to Hoekstra’s heart. It began in her garage back in 2005, when she and Weber first built large sandboxes in which captured mice could built their burrows. “We called them our phenodomes,” she says. The duo would then evict the mice and fill the burrows with an expanding foam (“We called it phenofoam”). The foam hardened into casts, which now fill the team’s attic space in their hundreds. The casts confirmed that the mice build incredibly consistent burrows, even if they had been raised in the lab and never seen sand before. It seemed likely that their home-building instincts were strongly influenced by their genes.

Jesse Weber with some phenofoam casts. By Ed Yong

Weber started looking into the genes behind the burrows by breeding oldfield mice with closely related deer mice. This species builds much simpler burrows with shorter entrances and no escape tunnel. These were probably the original specs, and the oldfield mouse added deluxe features during its evolution.

Today, the two species live in different habitats, but they can still mate if they meet one another. Weber found that these first-generation hybrids dig oldfield-style burrows, with long entrances and escape tunnels. This suggests that the alleles (version of a gene) behind the newer behaviours take dominance over their older counterparts.

Weber then mated the hybrids with more deer mice and analysed the genomes of these second-generation animals. He discovered three separate genetic regions that affect the length of the entrance tunnel. “We were pretty surprised,” says Hoekstra. “We definitely didn’t expect that each of those regions makes the burrow 3 centimetres longer, or that they work additively and contribute equally.”

On the other hand, Weber found that just one region governs the escape tunnel. If mice have at least one of the dominant oldfield alleles at this site, they are 30 percent more likely to build a getaway route, and around half of the second-generation hybrids did so. That makes the escape tunnel a “Mendelian trait”, where inheriting the dominant version of a gene from either parent produces the dominant form of the trait. Other examples include a cleft in your chin, or whether you can roll your tongue.

All four regions sit on separate chromosomes and are independent of one another. “These two components of a burrow–the entrance and escape tunnel—are completely separable,” says Hoekstra. This suggests that the complex nature of the burrow could have arisen by putting together different modules that evolved separately. “You don’t need all that many starting pieces but if you combine them in different ways you get a lot of diversity.”

“It’s great work. There are very few other examples of genes for naturally occurring variation in behaviour,” says Marla Sokolowski, who has found a few in fruit flies. “When I started similar work in the 1980s, I was told that there was no way I’d ever find a gene that influences behaviour that varies naturally. Their effects would be so small that you’d never find them.”

Oldfield mouse, by J.B. Miller, Florida Park Service

Three of Hoekstra’s lab members are now racing to find the specific genes responsible for the burrow architecture—each of the four regions might contain just one gene, or a cluster of them When that’s done, they can start to answer some burning questions. Remember that the entrance tunnel has to be just the right length, and the escape tunnel must go right up to the surface but never actually break through. So how does such a small number of genes control such seemingly complicated behaviour?

“That’s the million dollar question,” says Hoekstra. “Right now, it’s all speculation but our favourite candidate gene is one that could be involved in motivation or addictive behaviour. One hypothesis is that the two species of mice all have the same neural circuitry but one is more motivated to finish the product. But I don’t think it’s quite that simple.”

Hoekstra’s student Hilary Metz is studying the rodents’ behaviour and testing them with different drugs to see how they differ from the deer mice. “Anecdotally, we know that the oldfield mouse is more active, which is the inverse of what you’d expect if it was just a change in activity.”

Other lab members are following up on the discovery in different ways. (Hoekstra’s team are a model of interdisciplinary science, with many scientists from varying backgrounds, tackling the study of evolution from different angles.) Student Zain Ali is going to add back the old versions of the burrow-related regions into oldfield mice to see what happens. He’s also trying to see what parts of the rodents’ brains are activated when they burrow, and what genes are active in those areas. And Brant Peterson is putting the mice in narrow glass-paned ant farms, so he can actually film them burrowing and quantify any differences in their movements.  “He has even taken X-ray videos of these mice digging,” says Hoekstra.


* To clarify, they didn’t blow the mice out. They blew, which spooked the mice, which then jumped out on their own!

Reference: Weber, Peterson & Hoekstra. 2013. Discrete genetic modules are responsible for complex burrow evolution in Peromyscus mice. Nature http://dx.doi.org/10.1038/nature11816

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Reversible gene marks linked to reversible careers in bees

A different version of this story appears at The Scientist.

Honeybee workers spend their whole lives toiling for their hives, never ascending to the royal status of queens. But they can change careers. At first, they’re nurses, which stay in the hive and tend to their larval sisters. Later on, they transform into foragers, which venture into the outside world in search of flowers and food.

This isn’t just a case of flipping between tasks. Nurses and foragers are very distinct sub-castes that differ in their bodies, mental abilities, and behaviour – foragers, for example, are the ones that use the famous waggle dance. “[They’re] as different as being a scientist or journalist,” explains Gro Amdam, who studies bee behaviour. “It’s really amazing that they can sculpt themselves into those two roles that require very specialist skills.” The transformation between nurse and forager is significant, but it’s also reversible. If nurses go missing, foragers can revert back to their former selves to fill the employment gap.

Amdam likens them to the classic optical illusion (shown on the right) which depicts both a young debutante and an old crone. “The bee genome is like this drawing,” she says. “It has both ladies in it. How is the genome able to make one of them stand out and then the other?

The answer lies in ‘epigenetic’ changes that alter how some of the bees’ genes are used, without changing the underlying DNA. Amdam and her colleague Andrew Feinberg found that the shift from nurse to forager involves a set of chemical marks, added to the DNA of few dozen genes. These marks, known as methyl groups, are like Post-It notes that dictate how a piece of text should be read, without altering the actual words. And if the foragers change back into nurses, the methylation marks also revert.

Together, they form a toolkit for flexibility, a way of seeing both the crone and the debutante in the same picture, a way of eking out two very different and reversible skill-sets from the same genome.


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Under three layers of junk, the secret to a fatal brain disease

Writers often compare the human genome to a collection of recipes for making a person. Each gene contains the instructions for building a protein, and our thousands of proteins work together to build and maintain our bodies.

But if the genome is a recipe book, it’s one that was written without a good editor. It is riddled with typos, unnecessary repetitions and meaningless drivel. A miniscule proportion actually codes for proteins. The rest looks like a scrapyard. It contains the remnants of dead genes that are no longer used and have degenerated into nonsense. It contains jumping genes that hop around the genome under their own power, sometimes leaving copies of themselves behind. And it contains the remains of these jumping genes, which have lost their hopping ability and stayed in place.

These “non-coding sequences” are often called junk DNA, and for good reason. It seems that they’re largely useless… but not entirely so. Ever since these non-coding sequences were first discussed, scientists have suspected that some of them play fruitful roles in the body. Many examples have since come to light, and Francois Cartault and his colleagues have found the latest one. He has shown that one piece of supposed “junk” might explain why some people from a tiny French island die from a bizarre brain disease.


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OXTR gene produces differences in kind behaviour that people can spot in 20 seconds

Update: I’ve amended this post following some harsh critical comments on the study from geneticists on Twitter, which I really should have noted while going through the paper.

Our genes can influence our behaviour in delicate ways, and these effects, while subtle, are not undetectable. Scientists can pick them up by studying large groups of people, but individuals can sometimes be sensitive to these small differences.

Consider the OXTR gene. It creates a docking station for a hormone called oxytocin, which has far-ranging effects on our social behaviour. People carry either the A or G versions of OXTR, depending on the “letter” that appears at a particular spot along its length. People with two G-copies tend to be more empathic, sociable and sensitive than those with at least one A-copy. These differences are small, but according to a new study from Aleksandr Kogan at the University of Toronto, strangers can pick up on them after watching people for just a few minutes.


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The genetic side to chimpanzee culture

Chimp_babiesIf you watch chimpanzees from different parts of Africa, you’ll see them doing very different things. Some use sticks to extract honey from beehives, while others prefer leaves. Some use sticks as hunting spears and others use them to fish for ants. Some drum on branches to get attention and others rip leaves between their teeth.

These behaviours have been described as cultural traditions; they’re the chimp equivalent of the musical styles, fashion trends and social rules of humans. They stem from the readiness of great apes to ape one another and pick up behaviours from their peers. But a new study complicates our understanding of chimp cultures. Kevin Langergraber at the Max Planck Institute for Evolutionary Anthropology has found that much of this variation in behaviour could have a genetic influence.


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Genes and culture: OXTR gene influences social behaviour differently in Americans and Koreans


There are great plays and bad ones, but the playwright’s actual text is only one aspect of a production. The very same words can take on radically different meanings depending on the whims of the director, the abilities of the actors and the setting of the stage. The same is true of our genes and our environments. In cases where genes affect our behaviour, the same stretch of DNA can lead to very different deeds, depending on individual circumstances. Just as a production defines a play, environments and cultures alter the effects of certain genes.

Heejung Kim from the University of California has discovered a great example of this effect by studying a gene called OXTR (or the ‘oxytocin receptor’, in full). The gene creates a docking station for a hormone called oxytocin, which is involved in all sorts of emotions and social behaviours, from trust to sexual arousal to empathy.

Kim looked at a specific version of the OXTR gene, whose carriers are allegedly more social and sensitive. But this link between gene and behaviour depends on culture; it exists among American people, who tend to look for support in troubled times, but not in Korean cultures, where such support is less socially acceptable. Culture sets the stage on which the OXTR gene expresses itself. (more…)

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Good teachers help students to realise their genetic potential at reading

Teacher_writing_on_a_BlackboardGenetic studies suggest that genes have a big influence on a child’s reading ability. Twins, for example, tend to share similar reading skills regardless of whether they share the same teacher. On the other hand, other studies have found that the quality of teaching that a child receives also has a big impact on their fluency with the written word. How can we make sense of these apparently conflicting results? Which is more important for a child’s ability to read: the genes they inherit from their parents, or the quality of the teaching they receive?

According to a new study, the answer, perhaps unsurprisingly, is both. Genes do have a strong effect on a child’s reading ability, but good teaching is vital for helping them to realise that potential. In classes with poor teachers, all the kids suffer regardless of the innate abilities bestowed by their genes. In classes with excellent teachers, the true variation between the children becomes clearer and their genetic differences come to the fore. Only with good teaching do children with the greatest natural abilities reach their true potential.

This study demonstrates yet again how tired the “nature versus nurture” debate is. As I wrote about recently in New Scientist, nature and nurture are not conflicting forces, but partners that work together to influence our behaviour.

This latest choreography of genes and environment was decoded by Jeanette Taylor from Florida State University. She studied over 800 pairs of Florida twins in the first and second grades. Of the pairs, 280 are identical twins who share 100% of their DNA, and 526 are non-identical twins who share just 50% of their DNA. These twin studies are commonly used to understand the genetic influences of behaviour. If a trait is strongly affected by genes, then the variation in that trait should be less pronounced in the identical twins than the non-identical ones.


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The MAOA guide to misusing genetics

MAOAI’ve got a feature in the latest issue of New Scientist. It’s sort of a four-step guide to interpreting studies looking at genes and behaviour, using one particular gene as a case study. The piece is out today, but it harkens back to lines of thinking that began over a century ago.

Italy, 1876. The criminologist and physician Cesare Lombroso has just published L’uomo delinquente (The Criminal Man), a work that will define European understanding of criminal behaviour for several decades. Lombroso believed that some people were born criminals, whose penchant for crime was set from birth and who had diminished responsibility for their own misdeeds.

Skip forward 133 years, and Lombroso’s theories seem antiquated, even distasteful. Our modern understanding of biology has put paid to simplistic ideas about the origins of criminality and violence. Discoveries from the growing field of ‘behavioural genetics’ show us how nature and nurture conspire to influence our actions. But because of these same discoveries, the idea of the born criminal has resurfaced in modern Italy under a different guise, a century after Lombroso’s death.

Last year, Italian courts cut the sentence of a convicted murderer by one year, on the basis that his genetic make-up supposedly predisposed him to violence. The man, Abdelmalek Bayout, carried a version of a gene called monoamine oxidase A, or MAOA, which has been linked to aggression and violence. The gene has a history of controversy. It has been linked to gang membership and psychological disorders, and it has been used to define an entire ethnic group as warriors.

The story of MAOA is the perfect case study for how gradual revelations about the tango between genes and environment can be translated into unconvincing applications and overplayed interpretations. There is no better example of the dangerous state of modern behavioural genetics, no better poster child for how to miscommunicate, misinterpret and misuse genetic discoveries.

The feature takes the form of four lessons, each covering a different area of research or controversy around MAOA:

  1. A catchy name is bound to be misleading
  2. Nature and nurture are inextricably linked
  3. Beware of reinforcing stereotypes
  4. Genes do not dictate behaviour

Go read the article to find out more.


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Revisiting FOXP2 and the origins of language

Today, a new paper published in Nature adds another chapter to the story of FOXP2, a gene with important roles in speech and language. The FOXP2 story is a fascinating tale that I covered in New Scientist last year. It’s one of the pieces I’m proudest of so I’m reprinting it here with kind permission from Roger Highfield, and with edits incorporating new discoveries since the time of writing.

The FOXP2 Story (2009 edition)  

Imagine an orchestra full of eager musicians which, thanks to an incompetent conductor, produces nothing more than an unrelieved cacophony. You’re starting to appreciate the problem faced by a British family known as KE. About half of its members have severe difficulties with language. They have trouble with grammar, writing and comprehension, but above all they find it hard to coordinate the complex sequences of face and mouth movements necessary for fluid speech.

Thanks to a single genetic mutation, the conductor cannot conduct, and the result is linguistic chaos. In 2001, geneticists looking for the root of the problem tracked it down to a mutation in a gene they named FOXP2. Normally, FOXP2 coordinates the expression of other genes, but in affected members of the KE family, it was broken.

It had long been suspected that language has some basis in genetics, but this was the first time that a specific gene had been implicated in a speech and language disorder. Overeager journalists quickly dubbed FOXP2 “the language gene” or the “grammar gene”. Noting that complex language is a characteristically human trait, some even speculated that FOXP2 might account for our unique position in the animal kingdom. Scientists were less gushing but equally excited – the discovery sparked a frenzy of research aiming to uncover the gene’s role.

Several years on, and it is clear that talk of a “language gene” was premature and simplistic. Nevertheless, FOXP2 tells an intriguing story. “When we were first looking for the gene, people were saying that it would be specific to humans since it was involved in language,” recalls Simon Fisher at the University of Oxford, who was part of the team that identified FOXP2 in the KE family. In fact, the gene evolved before the dinosaurs and is still found in many animals today: species from birds to bats to bees have their own versions, many of which are remarkably similar to ours. “It gives us a really important lesson,” says Fisher. “Speech and language didn’t just pop up out of nowhere. They’re built on very highly conserved and evolutionarily ancient pathways.”

Two amino acids, two hundred thousand years

The first team to compare FOXP2 in different species was led by Wolfgang Enard from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. In 2001, they looked at the protein that FOXP2 codes for, called FOXP2, and found that our version differs from those of chimpanzees, gorillas and rhesus macaques by two amino acids out of a total of 715, and from that of mice by three. This means that the human version of FOXP2 evolved recently and rapidly: only one amino acid changed in the 130 million years since the mouse lineage split from that of primates, but we have picked up two further differences since we diverged from chimps, and this seems to have happened only with the evolution of our own species at most 200,000 years ago.

The similarity between the human protein FOXP2 and that of other mammals puts it among the top 5 per cent of the most conserved of all our proteins. What’s more, different human populations show virtually no variation in their FOXP2 gene sequences. Last year, Enard’s colleague Svante Pääbo made the discovery that Neanderthals also had an identical gene, prompting questions over their linguistic abilities (see “Neanderthal echoes below).

“People sometimes think that the mutated FOXP2 in the KE family is a throwback to the chimpanzee version, but that’s not the case,” says Fisher. The KEs have the characteristically human form of the gene. Their mutation affects a part of the FOXP2 protein that interacts with DNA, which explains why it has trouble orchestrating the activity of other genes.

There must have been some evolutionary advantage associated with the human form of FOXP2, otherwise the two mutations would not have spread so quickly and comprehensively through the population. What this advantage was, and how it may have related to the rise of language, is more difficult to say. Nevertheless, clues are starting to emerge as we get a better picture of what FOXP2 does – not just in humans but in other animals too.

During development, the gene is expressed in the lungs, oesophagus and heart, but what interests language researchers is its role in the brain. Here there is remarkable similarity across species: from humans to finches to crocodiles, FOXP2 is active in the same regions. With no shortage of animal models to work with, several teams have chosen songbirds due to the similarities between their songs and human language: both build complex sequences from basic components such as syllables and riffs, and both forms of vocalisation are learned through imitation and practice during critical windows of development.

Babbling birds

All bird species have very similar versions of FOXP2. In the zebra finch, its protein is 98 per cent identical to ours, differing by just eight amino acids. It is particularly active in a part of the basal ganglia dubbed “area X”, which is involved in song learning. Constance Scharff at the Max Planck Institute for Molecular Genetics in Berlin, Germany, reported that finches’ levels of FOXP2 expression in area X are highest during early life, which is when most of their song learning takes place. In canaries, which learn songs throughout their lives, levels of the protein shoot up annually and peak during the late summer months, which happens to be when they remodel their songs.

So what would happen to a bird’s songs if levels of the FOXP2 protein in its area X were to plummet during a crucial learning window? Scharff found out by injecting young finches with a tailored piece of RNA that inhibited the expression of the FOXP2 gene. The birds had difficulties in developing new tunes and their songs became garbled: they contained the same component “syllables” as the tunes of their tutors, but with syllables rearranged, left out, repeated incorrectly or sung at the wrong pitch.

The cacophony produced by these finches bears uncanny similarities to the distorted speech of the afflicted KE family members, making it tempting to pigeonhole FOXP2 as a vocal learning gene – influencing the ability to learn new communication sounds by imitating others. But that is no more accurate than calling it a “language gene”. For a start, songbird FOXP2 has no characteristic differences to the gene in non-songbirds. What’s more, among other species that show vocal learning, such as whales, dolphins and elephants, there are no characteristic patterns of mutation in their FOXP2 that they all share.

Instead, consensus is emerging that FOXP2 probably plays a more fundamental role in the brain. Its presence in the basal ganglia and cerebellums of different animals provides a clue as to what that role might be. Both regions help to produce precise sequences of muscle movements. Not only that, they are also able to integrate information coming in from the senses with motor commands sent from other parts of the brain. Such basic sensory-motor coordination would be vital for both birdsong and human speech. So could this be the key to understanding FOXP2?

Moving mice

New work by Fisher and his colleagues supports this idea. In 2008, his team engineered mice to carry the same FOXP2 mutation that affects the KE family, rendering the protein useless. Mice with two copies of the dysfunctional FOXP2 had shortened lives, characterised by motor disorders, growth problems and small cerebellums. Mice with one normal copy of FOXP2 and one faulty copy (as is the case in the affected members of the KE family) seemed outwardly healthy and capable of vocalisation, but had subtle defects.

For example, they found it difficult to acquire new motor skills such as learning to run faster on a tilted running wheel. An examination of their brains revealed the problem. The synapses connecting neurons within the cerebellum, and those in a part of the basal ganglia called the striatum in particular, were severely flawed. The signals that crossed these synapses failed to develop the long-term changes that are crucial for memory and learning. The opposite happened when the team engineered mice to produce a version of FOXP2 with the two characteristically human mutations. Their basal ganglia had neurons with longer outgrowths (dendrites) that were better able to strengthen or weaken the connections between them.

A battery of over 300 physical and mental tests showed that the altered mice were generally healthy. While they couldn’t speak like their cartoon equals, their central nervous system developed in different ways, and they showed changes in parts of the brain where FOXP2 is usually expressed (switched on) in humans.

Their squeaks were also subtly transformed. When mouse babies are moved away from their nest, they make ultrasonic distress calls that are too high for us to hear, but that their mothers pick up loudly and clearly. The altered Foxp2 gene subtly changed the structure of these alarm calls. We won’t know what this means until we get a better understanding of the similarities between mouse calls and human speech.

For now, the two groups of engineered mice tentatively support the idea that human-specific changes to FOXP2 affect aspects of speech, and strongly support the idea that they affect aspects of learning. “This shows, for the first time, that the [human-specific] amino-acid changes do indeed have functional effects, and that they are particularly relevant to the brain,” explains Fisher. “FOXP2 may have some deeply conserved role in neural circuits involved in learning and producing complex patterns of movement.” He suspects that mutant versions of FOXP2 disrupt these circuits and cause different problems in different species.

Pääbo agrees. “Language defects may be where problems with motor coordination show up most clearly in humans, since articulation is the most complex set of movements we make in our daily life,” he says. These circuits could underpin the origins of human speech, creating a biological platform for the evolution of both vocal learning in animals and spoken language in humans.

Holy diversity, Batman

The link between FOXP2 and sensory-motor coordination is bolstered further by research in bats. Sequencing the gene in 13 species of bats, Shuyi Zhang and colleagues from the East China Normal University in Shanghai discovered that it shows incredible diversity. Why would bats have such variable forms of FOXP2 when it is normally so unwavering in other species?

Zhang suspects that the answer lies in echolocation. He notes that the different versions seem to correspond with different systems of sonar navigation used by the various bat species. Although other mammals that use echolocation, such as whales and dolphins, do not have special versions of FOXP2, he points out that since they emit their sonar through their foreheads, these navigation systems have fewer moving parts. Furthermore, they need far less sensory-motor coordination than flying bats, which vocalise their ultrasonic pulses and adjust their flight every few milliseconds, based on their interpretation of the echoes they receive.

These bats suggest that FOXP2 is no more specific to basic communication than it is to language, and findings from other species tell a similar tale. Nevertheless, the discovery that this is an ancient gene that has assumed a variety of roles does nothing to diminish the importance of its latest incarnation in humans.

Since its discovery, no other gene has been convincingly implicated in overt language disorders. FOXP2 remains our only solid lead into the genetics of language. “It’s a molecular window into those kinds of pathways – but just one of a whole range of different genes that might be involved,” says Fisher. “It’s a starting point for us, but it’s not the whole story.” He has already used FOXP2 to hunt down other key players in language.

The executive’s minions

FOXP2 is a transcription factor, which activates some genes while suppressing others. Identifying its targets, particularly in the human brain, is the next obvious step. Working with Daniel Geschwind at the University of California, Los Angeles, Fisher has been trying to do just that, and their preliminary results indicate just what a massive job lies ahead. On their first foray alone, the team looked at about 5000 different genes and found that FOXP2 potentially regulates hundreds of these.

Some of these target genes control brain development in embryos and its continuing function in adults. Some affect the structural pattern of the developing brain and the growth of neurons. Others are involved in chemical signalling and the long-term changes in neural connections that enable to learning and adaptive behaviour. Some of the targets are of particular interest, including 47 genes that are expressed differently in human and chimpanzee brains, and a slightly overlapping set of 14 targets that have evolved particularly rapidly in humans.

Most intriguingly, Fisher says, “we have evidence that some FOXP2 targets are also implicated in language impairment.” Last year, Sonja Vernes in his group showed that FOXP2 switches off CNTNAP2, a gene involved in not one but two language disorders – specific language impairment (SLI) and autism. Both affect children, and both involve difficulties in picking up spoken language skills. The protein encoded by CNTNAP2 is deployed by nerve cells in the developing brain. It affects the connections between these cells and is particularly abundant in neural circuits that are involved in language.

Verne’s discovery is a sign that the true promise of FOXP2’s discovery is being fulfilled – the gene itself has been overly hyped, but its true worth lies in opening a door for more research into genes involved in language. It was the valuable clue that threw the case wide open. CNTNAP2 may be the first language disorder culprit revealed through FOXP2 and it’s unlikely to be the last.

Most recently, Dan Geschwind compared the network of genes that are targeted by FOXP2 in both chimps and humans. He found that the two human-specific amino acids within this executive protein have radically altered the set of genetic minions that it controls.

The genes that are directed by human FOXP2 are a varied cast of players that influence the development of the head and face, parts of the brain involved in motor skills, the growth of cartilage and connective tissues, and the development of the nervous system. All those roles fit with the idea that our version of FOXP2 has been a lynchpin in evolving the neural circuits and physical structures that are important for speech and language.

The FOXP2 story is far from complete, and every new discovery raises fresh questions just as it answers old ones. Already, this gene has already taught us important lessons about evolution and our place in the natural world. It shows that our much vaunted linguistic skills are more the result of genetic redeployment than out-and-out innovation. It seems that a quest to understand how we stand apart from other animals is instead leading to a deeper appreciation of what unites us.

Box – Neanderthal echoes

The unique human version of the FOXP2 gives us a surprising link with one extinct species. Last year, Svante Pääbo’s group at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, extracted DNA from the bones of two Neanderthals, one of the first instances of geneticists exploring ancient skeletons for specific genes. They found that Neanderthal FOXP2 carries the same two mutations as those carried by us – mutations accrued since our lineage split from chimps between 6 and 5 million years ago.

Pääbo admits that he “struggled” to interpret the finding: the Neanderthal DNA suggests that the modern human’s version of FOXP2 arose much earlier than previously thought. Comparisons of gene sequences of modern humans with other living species had put the origins of human FOXP2 between 200,000 and 100,000 years ago, which matches archaeological estimates for the emergence of spoken language. However, Neanderthals split with humans around 400,000 years ago, so the discovery that they share our version of FOXP2 pushes the date of its emergence back at least that far.

“We believe there were two things that happened in the evolution of human FOXP2,” says Pääbo. “The two amino acid changes – which happened before the Neanderthal-human split – and some other change which we don’t know about that caused the selective sweep more recently.” In other words, the characteristic mutations that we see in human FOXP2 may indeed be more ancient than expected, but the mutated gene only became widespread and uniform later in human history. While many have interpreted Pääbo’s findings as evidence that Neanderthals could talk, he is more cautious. “There’s no reason to assume that they weren’t capable of spoken language, but there must be many other genes involved in speech that we yet don’t know about in Neanderthals.”


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Genes affect our likelihood to punish unfair play

This article is reposted from the old WordPress incarnation of Not Exactly Rocket Science. The blog is on holiday until the start of October, when I’ll return with fresh material.

As a species, we value fair play. We’re like it so much that we’re willing to eschew material gains in order to punish cheaters who behave unjustly. Psychological games have set these maxims in stone, but new research shows us that this sense of justice is, to a large extent, influenced by our genes.

When it comes to demonstating our innate preference for fair play, psychologists turn to the ‘Ultimatum Game‘, where two players bargain over a pot of money. The ‘proposer’ suggests how the money should be divided and the ‘receiver’ can accept of refuse the deal. If they refuse, neither player gets anything and there is no room for negotiation. In a completely rational setting, the proposer should offer the receiver as little as possible, and the receiver should take it – after all, a very little money is better than none at all.

Of course, that’s not what happens. Receivers typically abhor unfair offers and would rather that both parties receive no money than accept a patronisingly tiny amount. Across most Western countries, proposers usually offer the receivers something between 40% and 50% of the takings. Any offers under 10% are almost always rejected.

The uniformity of responses across Western countries suggests that culture has a strong effect on how people play the game, but until now, no one had looked to see how strongly genes asserted their influence. Bjorn Wallace and colleagues from the Stockholm School of Economics decided to do just that, and they used the classic experiment for working out heritability – the twin study.


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Child abuse permanently modifies stress genes in brains of suicide victims

Blogging on Peer-Reviewed ResearchThe trauma of child abuse can last a lifetime, leading to a higher risk of anxiety, depression and suicide further down the line. This link seems obvious, but a group of Canadian scientists have found that it has a genetic basis.

By studying the brains of suicide victims, Patrick McGowan from the Douglas Mental Health University Institute, found that child abuse modifies a gene called NR3C1 that affects a person’s ability to deal with stress. The changes it wrought were “epigenetic”, meaning that the gene’s DNA sequence wasn’t altered but it’s structure was modified to make it less active. These types of changes are very long-lasting, which strongly suggests that the trauma of child abuse could be permanently inscribed onto a person’s genes.

Child abuse, from neglect to physical abuse, affects the workings of an important group of organs called the “hypothalamic-pituitary-adrenal axis” or HPA. This trinity consists of the hypothalamus, a funnel-shaped part of the brain; the pituitary gland, which sits beneath it; and the adrenal glands, which sit above the kidneys.  All three organs secrete hormones. Through these chemicals, the HPA axis controls our reactions to stressful situations, triggering a number of physiological changes that prime our bodies for action.

The NR3C1 gene is part of this system. It produces a protein called the glucocorticoid receptor, which sticks to cortisol, the so-called “stress hormone”. Cortisol is produced by the adrenal glands in response to stress, and when it latches on to its receptor,  it triggers a chain reaction that deactivates the HPA axis. In this way, our body automatically limits its own response to stressful situations.

Without enough glucocorticoid receptors, this self-control goes awry, which means that the HPA is active in normal situations, as well as stressful ones. No surprise then, that some scientists have found a link between low levels of this receptor and schizophrenia, mood disorders and suicide. So, childhood trauma alters the way the body reacts to stress, which affects a person’s risk of suicide or mental disorders later in life. Now, McGowan’s group have revealed part of the genetic (well, epigenetic) basis behind this link.


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Ask an IVF baby: does smoking while pregnant lead to antisocial behaviour?

Blogging on Peer-Reviewed ResearchOur health isn’t just affected by the things we do after we’re born – the conditions we face inside our mother’s womb can have a lasting impact on our wellbeing, much later in life. This message comes from a growing number of studies that compare a mother’s behaviour during pregnancy to the subsequent health of her child.

But all of these studies have a problem. Mothers also pass on half of their genes to their children, and it’s very difficult to say which aspects of the child’s health are affected by conditions in the womb, and which are influenced by mum’s genetic legacy.

Take the case of smoking. Doing it while pregnant is bad news for the foetus, and studies have suggested that children whose mothers smoke during pregnancy are more likely to be born prematurely, be born lighter, have poorer lung function, and be more likely to die suddenly before their first birthday. More controversially, they may even show higher levels of behavioural problems including autistic disorders and antisocial tendencies.

Biologically, these results make sense, but many of these risks can be inherited too. For example, genetic factors can strongly influence both a person’s susceptibility to nicotine addiction and their propensity for violent behaviour. A mother’s genes could also affect the birth weight of her child.

To untangle these influences, the ideal experiment would involve randomly implanting foetuses either in the wombs of their own mothers, or those of unrelated women.  That’s possible in animals but deliberately doing so in humans would be both unethical and impractical. Nonetheless, Frances Rice from Cardiff University realised that this experiment was actually well underway.

Since the advent of in vitro fertilisation (IVF) technology in the late 1970s, many mothers have nourished babies in their womb, who weren’t genetically related to them. Here was an ideal chance to study the effects of conditions in the womb, without any confusion caused by shared genes.


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Saucy study reveals a gene that affects aggression after provocation

Blogging on Peer-Reviewed ResearchPeople seem inordinately keen to pit nature and nurture as imagined adversaries, but this naive view glosses over the far more interesting interactions between the two. These interactions between genes and environment lie at the heart of a new study by Rose McDermott from Brown University, which elegantly fuses two of my favourite topics – genetic influences on behaviour and the psychology of punishment.

<Regular readers may remember that I've written three previous pieces on punishment. Each was based on a study that used clever psychological games to investigate how people behave when they are given a choice to cooperate with, cheat, or punish their peers.

McDermott reasoned that the way people behave in these games might be influenced by the genes they carry and especially one called monoamine oxidase A (MAOA), which has been linked to aggressive behaviour. Her international team of scientists set out to investigate the effect that different versions of MAOA would have in a real situation, where people believe that they actually have the chance to hurt other people.

MAOA encodes a protein that helps to break down a variety of signalling chemicals in the brain, including dopamine and serotonin. It has been saddled with the tag of “warrior gene” because of its consistent link with aggressive behaviour. A single fault in the gene, which leads to a useless protein, was associated with a pattern of impulsive aggression and violent criminal behaviour among the men of a particular Dutch family. Removing the gene from mice makes them similarly aggressive.

These are all-or-nothing changes, but subtler variations exist. For example, there is a high-activity version of the gene (MAOA-H), which produces lots of enzyme and a low-activity version (MAOA-L), which produces very little. The two versions are separated by changes in the gene’s “promoter region”, which controls how strongly it is activated.

A few years ago, British scientists found that children who had been abused are less likely to develop antisocial problems if they carry the MAOA-H gene than if those who bear the low-activity MAOA-L version. An Italian group has since found the same thing. It is a truly fascinating result for it tells us that the MAOA gene not only affects a person’s behaviour, but also their reactions to other people’s behaviour.

But both studies had a big flaw – they measured aggression by asking people to fill in a questionnaire. Essentially, they relied on people to accurately say how belligerent they are and we all know that many people like to talk big. McDermott wanted to look at actions not claims.

To that end, she recruited 78 male volunteers and sequenced their MAOA gene to see which version they carried (just over a quarter had the low-activity version). The volunteers played out a scenario where they believed that they could actually physically harm another person for taking money that they had earned. Their weapon of retribution? Spicy sauce.


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Of voles and men: exploring the genetics of commitment

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Love is all around us and love is in the air, and if I know my mainstream science reporters, today they will have you believe that love is in our genes too. A new report suggests that variation in a gene called AVPR1A has a small but evident influence on the strength of a relationship, the likelihood of tying the knot and the risk of divorce. It’s news for humans, but it’s well-known that the gene’s rodent counterpart affects the bonds between pairs of voles. The story really starts with these small rodents and it’s them that I now turn to.

Prairie-voles.jpgVoles make unexpectedly good animals to study if you’re interested in the genetic basis of commitment, because closely related species have very different mating strategies. The prairie vole is (mostly) monogamous; males and females mate for life and look after their pups with great care. On the other hand, the closely related meadow and montane voles have more of the love-rat about them – males have many mates, flit between them and take no responsibility for the care of their many young.

Behind these different behaviours lie is a hormone called vasopressin and its partner molecule – the vasopressin receptor V1aR. Vasopressin is a neurotransmitter – a signalling molecule of the brain – and it transmits signals by attaching to V1aR, like a key fitting into a lock. Alter the balance of these molecules and you can change the voles’ behaviour. For example, give extra vasopressin to a prairie vole and it will develop a stronger bond with its partner, but block the receptor and you break the bond.

It even works in the promiscuous meadow voles. Prairie voles have much higher levels of the vasopressin receptor than meadow voles do and in 2004, Miranda Lim loaded the forebrains of meadow vole males with extra copies of V1aR  to the same levels of their prairie cousins. The males were paired with a female and when they had to choose between her and a newcomer, those that packed extra V1aR spent most of their time with their familiar partners. Those that were injected with a random gene, unrelated to monogamy, stuck to their old promiscuous ways.